.In the management of congenital heart disease (CHD) has markedly reduced mortality. However, brain injury remains a major impediment to high quality of life in survivors. A growing body of literature suggests that a substantial component of this neurologic morbidity may be prenatal in origin. Our studies in CHD fetuses showed for the first time that impaired brain development occurs predominantly in the third trimester and is associated with evidence of impaired brain perfusion and anaerobic metabolism. The mechanism by which CHD disrupts fetal brain development remains unclear. We have developed and validated methods to safely and reliably quantify brain development and metabolism in the living fetus, and newborn using advanced magnetic resonance imaging (MRI) techniques. In the current proposal, we plan to apply echocardiographic measures of the fetal circulation (as well as quantitative MRI methods) to identify the earliest biomarkers for impaired brain development in the fetus with CHD. We will accomplish this by addressing the following specific aims: 1) to determine whether abnormalities in cortical development and brain metabolism (by quantitative MRI and Magnetic Resonance Spectroscopy) are an early marker for risk of impaired volumetric brain growth in the fetus with CHD compared to control fetuses, 2) to determine whether systemic and cerebral hemodynamic perfusion abnormalities (by echocardiography/Doppler US) predict impaired brain growth and/or elevated cerebral lactate in the fetus with CHD versus controls, and 3) to examine the early and long-term neurodevelopmental significance of fetal biomarkers for impaired brain development identified in aims 1 and 2. Our goal is to develop the capacity to reliably and non-invasively identify fetuses with CHD at risk for early brain injury. This, in turn, will begin to open windows for the development of therapeutic interventions aimed at preventing or limiting impaired brain development in these high-risk fetuses.